It is generally agreed that cortical processing of nociceptive stimuli is responsible for the more complex, non-reflexive, and clinically relevant aspects of pain. Human imaging studies are demonstrating the importance of specific cortical areas in nociception, the insular cortex in particular. Presently the neural circuits through which the cortex is involved in nociceptive processing remain largely unknown. We have previous identified a region within the insular cortex of the rat, the rostral agranular insular cortex (RAIC), which is involved in modulation of pain behavior. This proposal examines the neural mechanisms involved in RAIC mediated antinociception. Our most recent work has demonstrated that blocking dopamine reuptake in the RAIC, which receives dense dopaminergic innervation, produces sustained behavioral antinociception and inhibition of cell activity in nociceptive areas of the spinal cord. As a continuation of these studies, the aims of the present proposal are designed to test the following specific hypotheses: (1) that decreasing dopamine inhibition in the RAIC increases cellular activity in nociceptive areas of the brain; (2) that dopamine mediated antinociception in the RAIC involves GABAergic neurotransmission; (3) that thalamic afferents directly control the release of dopamine in the RAIC; and finally, (4) that dopamine is responsible for the antinociceptive effect of catecholamines in the RAIC independently of noradrenergic transmission. The present proposal will identify neural circuits involved in dopamine antinociception from the RAIC. While the role of dopamine in the forebrain has been the subject of extensive research in relatio9n to mood disorders and degenerative diseases, the present proposal is the first to examine the involvement of cortical dopaminergic neurotransmission in nociception. The clinical implications of loss of dopaminergic inhibition of the cerebral cortex include central pain syndromes such as those reported in Parkinson's disease and in patients treated with neuroleptic drugs.